Mechanism of cooperative clonal evolution of ATL by genomic and epigenomic abnormalities

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K08386
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: The University of Tokyo
• Principal Investigator: Yamagishi Makoto 東京大学, 大学院新領域創成科学研究科, 准教授 (90625261)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: HTLV-1 / ゲノム / エピゲノム / ATL / がん / クローン進化

Outline of Final Research Achievements

We performed gene expression analyses in HTLV-1-infected individuals and demonstrated that the fundamental properties underlying ATL cells are formed in the HTLV-1 carriers. We also showed that Tax causes genome-wide changes in the epigenetic properties of host cells, indicating that epigenomic characteristics essential for tumorigenesis are established early in the development of tumor cells. Furthermore, we showed that infected cells undergo a process of clonal evolution into tumor cells by gradually acquiring genetic mutations during a long-term latent period (Nat Commun 2021). Furthermore, we demonstrated that an abnormal pattern of EZH1/2-dependent H3K27me3 formed in infected cells is critical in tumorigenesis. The development of a novel EZH1/2 inhibitor targeting this epigenomic abnormality was successfully achieved (Nature 2024).

Free Research Field

分子生物学

Academic Significance and Societal Importance of the Research Achievements

本研究の成果により、ATLの発症に至る長期過程においてゲノムおよびエピゲノムに蓄積する異常の全体像が示され、特に初期形成されるエピゲノム異常の重要性が明らかになった。またこのエピゲノム異常を標的としたEZH1/2阻害薬バレメトスタットが、多数のゲノム異常が蓄積したATL症例に対して有効であったことが臨床的に示され、さらにその作用機序も明らかになったことは、学術的、臨床的意義が大きく、基礎的な理解を踏まえた新しい治療の確立に繋がった。